Pathology of Head and Neck Tumors

MANJU L. PRASAD, MD ANDREW G. HUVOS, MD

TUMORS OF THE UPPER AERODIGESTIVE TRACT MUCOSA

Neoplasias of the upper aerodigestive tract histologically tend to mimic the normal constituent cells in this region. The most common neoplasias show differentiation toward lining epithelium.

pressure. Synchronous or metachronous association with squamous cell carcinoma as well as progression to it may occur in some patients with inverted

Benign Papillary Lesions

Squamous papilloma is a solitary papillary lesion of the squamous epithelium which has a white, frondlike gross appearance. Microscopically, it consists of multiple papillae of benign, stratified squamous cells arranged around central fibrovascular cores. They usually occur in adults. Although a viral etiology is suspected, human papillomavirus (HPV) types 6 and/or 11 have been detected in only some of the cases. Juvenile laryngeal papillomatosis are his-tologically similar to squamous papilloma but occur in children and are characteristically multiple. They tend to recur and sometimes can be florid enough to cause asphyxiation. Sometimes the recurrences cease at puberty. Squamous cell carcinoma may follow radiation therapy for treatment ofjuvenile papillomatosis (Figure 2-1).

Schneiderian papillomas arise in the sinonasal region and may be fungiform (exophytic), inverted (endophytic) or oncocytic (Figure 2-2). The role of HPV in their development is controversial. The patients are middle-aged. Although benign, the recurrence rate with local excision is almost 70 percent. The inverted papilloma may erode bone by

Figure 2-1. Infiltrating squamous cell carcinoma developing in a solitary tracheal papilloma in a 31-year-old male. The papillary lesion occupied the anterior half of the tracheal lumen. The carcinoma infiltrated the anterior wall of the trachea. The patient had a benign solitary tracheal papilloma since the age of 2 and had suffered many recurrences.

and oncocytic papillomas. The histologic appearance does not help in predicting the occurrence of recurrence or carcinomatous change.1

Verruca vulgaris and condyloma can be seen in the oral mucosa and their appearance is similar to that occurring elsewhere in the body.

Malignant and Premalignant Squamous Cell Lesions

Squamous cell carcinoma (SCC) is the most common malignant tumor of the upper aerodigestive mucosa, and shows a distinct male predilection. Tobacco and alcohol consumption are significant risk factors. Several HPV DNA subtypes have been found in association with SCC; however, their role in carcinogenesis remains conjectural.

Precancerous Lesions

Leukoplakia is a whiter patch on the oral mucosa which cannot be scraped off; nor can it be attributed to any other disease entity. Histologically, it is represented by hyperkeratosis with acanthosis with or without dysplasia. Erythroplakia is a red, velvety mucosal patch that represents epithelial atrophy, inflammation and subepithelial telangiectasia. Ery-throplakia or erythroleukoplakia (speckled white and red patches) confer a greater risk of being associated with dysplasia with 91 percent being in situ or invasive SCC.2,3 Proliferative verrucous leukoplakia (PVL) is an idiopathic condition occurring typically in the oral mucosa of elderly women which pursues a recurrent and progressive clinical course. Histo-logically, it appears with innocuous hyperkeratosis of the squamous epithelium and progresses to verru-cous hyperplasia and dysplasia with the ultimate development of verrucous or conventional SCC over a protracted period of time.4 This has led some to advocate that verrucous hyperplasia, the earliest his-tologically definable event in PVL, should be treated like verrucous carcinoma.5

Dysplasia is architecturally disordered proliferation of epithelial cells displaying abnormal cytologic appearance and maturation. Graded along a 3-tier system, mild dysplasia manifests as an increase in mitotic activity in the basal layer. It is difficult to distinguish it from reactive/repair activity of the squa mous epithelium. Suprabasal mitosis heralds moderate dysplasia, the diagnosis of which may be aided by immunohistochemical staining for cell proliferation markers, eg, Ki-67 (MIB1) and proliferating cell nuclear antigen (PCNA). Overexpression of p53, although uncommon, signifies malignant transformation of moderate dysplasia to carcinoma in situ.6

Carcinoma in Situ

Carcinoma in situ (CIS)/severe dysplasia of the oral mucosa is usually of the keratinizing type, in which the abundant eosinophilic cytoplasm continues to show some degree of differentiation as the atypical epithelial cells migrate from basal to more superficial layers while still retaining their mitotic activity. The basaloid type, in which atypical, undifferentiated, basaloid cells with high nuclear cytoplasmic ratio

Atrophic Oral Dysplasia
Figure 2-2. Fungiform schneiderian papilloma. The lesion is exophytic, lined with multiple layers of cells with a morphology transitional between squamous and columnar cells. Mucous cells containing blue mucin are scattered throughout. Acute and chronic inflammation is characteristically present.
Dysplasia Oral Mucosa
Figure 2-3. Carcinoma in situ/severe dysplasia in atrophic laryngeal mucosa. Dysplastic cells with hyperchromatic nuclei and increased nuclear cytoplasmic ratio are present even in the superficial layer of the squamous mucosa. The basement membrane is intact.

occupy all layers of the epithelium, is usually seen in the oropharynx and the larynx (Figure 2-3).

Field cancerization is the appearance of multiple synchronous or metachronous primary carcinomas in a mucosal field exposed to the same local carcinogen. The synchronous lesions are separated by so-called skip areas of histologically normal mucosa. Metachronous second primary lesions are accompanied by CIS.

Invasive Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) consists of malignant cells with squamous differentiation as evinced by the presence of intercellular bridges and keratin formation. The conventional SCC is histologically graded on a scale of 3: well-, moderately- and poorly-differentiated SCC, depending upon the presence of intra- and extracellular keratin. However, this scheme has little bearing on prognosis. Better prognostic indicators and predictors of lymph node metastasis are enumerated in Table 2-1. Excellent prognosis is expected for so-called thin tumors versus thick ones, ie, less than 1.5 mm in the floor of the mouth,7 2 mm in the tongue,8 and 3 mm in the buccal mucosa.9 Tumor thickness is an independent predictor of recurrence, lymph node metastasis and survival. It has been shown that when the invasive front is well demarcated, blunt and of pushing type (grade 1) (Figure 2-4), the tumors have a better prognosis and lower rate of lymph node metastasis than when it is jagged, irregularly infiltrative in the form of short cords and even single cells (grade 3 to 4) (Figure 2-5).10,11 Assessment of surgical margins by intraoperative pathology consultation helps ensure complete removal of tumor. In situ or invasive carcinoma at or close (less than 5 mm) to the inked margin of resection increases the risk of recurrence and may require postsurgical radiotherapy. Tumors of the lower alveolar ridge infiltrate the mandible by direct extension and either spread between the medullary bony trabeculae or perineu-rally around the inferior alveolar nerve. The latter is significantly more common in edentulous patients than in the dentate ones. The mandibular extension

Table 2-1. PATHOLOGIC PROGNOSTIC FACTORS

IN UPPER AERODIGESTIVE SQUAMOUS

CELL CARCINOMA

Factors Related

Factors Related to

to Primary Tumor

Regional Lymph Nodes

Size

Positive/negative

Thickness

Number of positive nodes

Invasive front

Size of largest positive node

Vascular and perineural invasion

Laterality of positive nodes

Margins of resection

Presence/absence of

Morphology

extracapsular extension

Well/poorly differentiated

Exophytic/endophytic

Mitotic index

Presence of carcinoma in situ

and multifocality

is, however, limited and corresponds to the extent of the tumor in the overlying mucosa.12

In node-positive carcinomas, the number of positive nodes, their location and the size of the largest positive lymph node are important predictors of survival. The presence of extracapsular extension of tumor is a poor prognostic feature requiring postsur-gical radiotherapy (see Table 2-1). Some conventional SCC may show cystic degeneration, pseudoglands and extracellular mucinous substance, but intracytoplasmic mucin is not seen in SCC. Several variants of SCC are recognized.

Verrucous carcinoma is an exophytic, warty, low-grade, well-differentiated SCC predominantly occurring in men in their seventh decade of life. It has a well-defined, broad, pushing invasive front. The cytomorphology of tumor cells is bland (Figure 2-6). Therefore, a superficial biopsy may not establish the

Figure 2-4. Moderately-differentiated squamous cell carcinoma of the tongue with a pushing type (grade 1) of infiltrating pattern at the tumor's growing edge.

diagnosis, as it may not include the invasive base of the tumor which is essential for a histologic diagnosis. The prognosis is excellent, marred only by local recurrences. Pure verrucous carcinoma does not have metastatic potential. However, approximately 20 percent of verrucous carcinomas are hybrid, having an additional component of conventional SCC that confers metastatic potential to it.13

Papillary SCC is also exophytic but has a frondlike appearance with a central fibrovascular core usually lined by layers of poorly-differentiated tumor cells. Infiltration of the stroma and/or the base of the neoplasm is necessary to establish invasion (Figure 2-7).

Basaloid SCC usually arises in the posterior oral cavity and is highly aggressive. These patients fare much worse as compared to even the poorly-differentiated SCC in terms of metastasis and survival. Nodal

Squamous Cell Carcinoma The Tongue
Figure 2-5. Moderately-differentiated squamous cell carcinoma of the tongue infiltrating the lamina propria. The invasive front shows a grade 3 infiltrating pattern by small clusters and cords of malignant cells.

Figure 2-4. Moderately-differentiated squamous cell carcinoma of the tongue with a pushing type (grade 1) of infiltrating pattern at the tumor's growing edge.

Are Squamous Cell Cancer Fast Growing
Figure 2-6. Verrucous carcinoma of the vocal cord. The malignant squamous cells are extremely well-differentiated with maturation and abundant keratinization toward the surface. The deep edge of the tumor is broad and of the pushing type. Grossly, the carcinoma was exophytic and warty.

metastasis is detected at initial presentation in almost two-thirds of the patients, and one-half of them develop distant metastasis with the lung being the most common site. This mandates a metastatic survey at initial diagnosis.14 Median survival is 18 months.15 Sarcomatoid (spindle cell) SCC is usually exo-phytic and polypoid with the same clinical profile as conventional SCC. Histologically, the tumor has remarkable resemblance to malignant fibrous histiocytoma. Lymph node metastasis can show either or both epithelial and sarcomatous components. Immunohistochemically, cytokeratin can be demonstrated in the epithelial as well as spindle cell components. Ultrastructurally, tonofilaments and des-mosomes, two of the hallmarks of squamous cells,

Papillary Nasopharyngeal Carcinoma

Figure 2-7. Papillary squamous cell carcinoma of the tongue. The tumor is exophytic with a focus of infiltration in the lamina propria. The papillae have fibrovascular cores and are lined by non-kera-tinizing moderately-differentiated squamous carcinoma cells in contrast with verrucous carcinoma. The prognosis is worse than the ver-rucous carcinoma as this tumor has metastatic capabilities.

Figure 2-7. Papillary squamous cell carcinoma of the tongue. The tumor is exophytic with a focus of infiltration in the lamina propria. The papillae have fibrovascular cores and are lined by non-kera-tinizing moderately-differentiated squamous carcinoma cells in contrast with verrucous carcinoma. The prognosis is worse than the ver-rucous carcinoma as this tumor has metastatic capabilities.

have been demonstrated in the spindle cells. Expression of smooth muscle actin and occasionally desmin points to myofibroblastic differentiation of the spindle cells.16

Adenocarcinoma and adenosquamous carcinoma of the upper aerodigestive tract are believed to arise in the submucosal glands. They may resemble salivary gland tumors and are discussed in that section.

Undifferentiated Carcinoma

Lymphoepithelial carcinoma occurs most commonly in the nasopharynx where it is also designated as World Health Organization (WHO) type 3 nasopharyngeal carcinoma (Table 2-2). Cervical lymph

Table 2-2. CLASSIFICATION OF NASOPHARYNGEAL CARCINOMA WORLD HEALTH ORGANIZATION, 1991

1. Squamous cell carcinoma, keratinizing

2. Non-keratinizing carcinoma

A. Differentiated non-keratinizing carcinoma

B. Undifferentiated carcinoma node metastasis from an occult primary is a frequent presentation. There is a bimodal age distribution with peaks in the second and sixth decades. There is a predilection for people of southern China and a well-established association with Epstein-Barr virus (EBV) infection.17 The tumor is heavily infiltrated by lymphocytes and sometimes eosinophils and may mimic Hodgkin's or non-Hodgkin's lymphoma (Figure 2-8). The sinonasal undifferentiated carcinoma (SNUC) usually occurs in middle-aged patients and has a slight female preponderance. The tumor is characterized by numerous mitoses, necroses and extensive vascular invasion—features supportive of its high-grade nature (Figure 2-9).

Lymphoma

The sinonasal region is the most frequent site for lymphomas of the upper aerodigestive tract, most of which are diffuse large B-cell lymphomas with clin-

icopathologic characteristics similar to anywhere else in the body. The nasal NK/T-cell lymphomas (synonyms: polymorphic reticulosis, angiocentric lymphoma, lethal midline granuloma) is a distinct clinicopathologic entity affecting Asians and Native Americans. It is a destructive sinonasal disease presenting usually in the midline. It is a tumor of the natural killer cells and T cells, and is frequently associated with EBV infection. The prognosis is extremely poor in Asians and Native Americans in contrast to Caucasians.

Plasmacytoma, either solitary or in association with multiple myeloma, may occur in relation to the upper aerodigestive tract. It may be associated with amyloid.

Neuroendocrine carcinoma and malignant melanoma are discussed in a separate section on tumors of neurogenic origin.

TUMORS OF THE SALIVARY GLANDS

The distribution of tumors among different salivary glands studied at the Memorial Sloan-Kettering Cancer Center is given in Figure 2-10.18 Benign tumors occur more frequently in the parotid glands of women in their fourth to fifth decades of life (Figure 2-11). Tumors in the minor salivary glands are

Figure 2-8. Lymphoepithelial carcinoma of the nasopharynx. The tumor cells have large, vesicular nuclei with prominent nucleoli and indistinct cytoplasm. They appear to be in a syncytium with an intimate admixture of lymphocytes (Schmincke pattern). Another pattern (not seen here) consists of cells arranged in loosely cohesive groups (Regaud pattern).

Figure 2-8. Lymphoepithelial carcinoma of the nasopharynx. The tumor cells have large, vesicular nuclei with prominent nucleoli and indistinct cytoplasm. They appear to be in a syncytium with an intimate admixture of lymphocytes (Schmincke pattern). Another pattern (not seen here) consists of cells arranged in loosely cohesive groups (Regaud pattern).

Figure 2-11. Relative distribution of benign versus malignant tumors among 1,875 parotid tumors at the Memorial Sloan-Kettering Cancer Center, New York.

K i I
Sinonasal Adenocarcinoma
Figure 2-9. Sinonasal undifferentiated carcinoma (SNUC). Poorly-differentiated tumor cells with central comedo-type necrosis infiltrating bone.

more likely to be malignant than parotid tumors (see Figure 2-11). Salivary gland tumors tend to recapitulate the normal histology of the salivary glands (Figure 2-12).

Figure 2-10. Relative distribution of 2,743 salivary gland tumors at the Memorial Sloan-Kettering Cancer Center, New York.

Figure 2-11. Relative distribution of benign versus malignant tumors among 1,875 parotid tumors at the Memorial Sloan-Kettering Cancer Center, New York.

Pleomorphic Adenoma

Pleomorphic adenoma or benign mixed tumor is the most frequent of parotid tumors. It occurs usually in the third to fifth decades with a female preponderance. The usual history is that of a slow growing tumor present for a long time. Grossly, the tumor is usually located in the superficial lobe of the parotid gland, and is well circumscribed with a gray-white, lobulated cut surface (Figure 2-13A). Histologically, it is composed of a varied mixture of epithelial and stromal components giving rise to its name "pleomorphic" or "mixed" tumor (Figure 2-13B). The tumor is believed to arise in the myoepithelial cells

Histology Ducts Scheme

Figure 2-12. Schematic diagram of the histology of the normal salivary gland. A uniform layer of myoepithelial cells invests the terminal secretory unit—the acinus and the intercalated duct.

Figure 2-10. Relative distribution of 2,743 salivary gland tumors at the Memorial Sloan-Kettering Cancer Center, New York.

Figure 2-12. Schematic diagram of the histology of the normal salivary gland. A uniform layer of myoepithelial cells invests the terminal secretory unit—the acinus and the intercalated duct.

Figure 2-13. A, Pleomorphic adenoma. The tumor has a nodular external surface and a gray-white cut surface which may display focal chondroid differentiation. B, Histology shows prominent blue mucinous/myxoid component with small cuboidal bland cells forming cords and duct-like structures.

which retain their capacity for dual differentiation. Although these tumors are well-circumscribed, multiple microscopic pseudopods of the tumor can be left behind if resected by "shelling out" which can lead to multifocal recurrences. A cellular mixed tumor has an excess of epithelial and myoepithelial cells with sparse chondromucinous stroma.

Malignant transformation occurs in 5 to 10 percent of cases and is much more common than the de novo malignant mixed tumor. Clinically, recent rapid growth and nerve palsy, while microscopically, cellular atypia, mitosis, invasion of the surrounding tissue, nerves and vessels constitute features of malignancy. Although both the epithelial and the mesenchymal components of the mixed tumor can undergo malignant transformation, the former is much more frequent, giving rise to the designation "carcinoma ex mixed tumor" and "carcinoma ex pleomorphic adenoma." They represent about 11 percent of all malignant salivary gland neoplasms.19 The patients are usually in their fifth decade with a slight female predilection. Most tumors are more than 3 cm in size. Important histologic prognostic factors are morphology of carcinoma (low vs. high grade) and degree of infiltration (in situ or minimally vs. extensively invasive).20 Almost all patients have local treatment failure. Distant metastasis can occur in 33 percent of cases, with lungs and bones being common sites. The less commonly occurring biphasic carcinosarcoma or "true" malignant mixed tumor has a very aggressive and lethal behavior.21

Monomorphic Adenoma

Monomorphic adenomas are relatively uncommon benign epithelial tumors predominantly occurring in the parotid glands. They lack the myxoid stroma of the pleomorphic adenoma. Various morphologic types are described. The canalicular adenoma occurs most frequently in the upper lip. The basal cell adenoma is composed of basal cells surrounded by a thick, hyaline basement membrane material containing stroma. The malignant counterpart, basal cell adenocarcinoma, is characterized by an infiltrative growth pattern.

Oncocytic Tumors

The parotid gland is the most common site for onco-cytic tumors which tend to occur in the fifth to sixth decades and which have shown a relationship to previous radiation exposure. Oncocytomas are solid tumors composed of cells with abundant mitochondria-rich cytoplasm which is intensely eosinophilic and granular in texture (Figure 2-14). The much more common papillary and cystic Warthin's tumor has a male predilection and a strong association with smoking. A characteristic non-neoplastic lympho-cytic component with activated follicles containing germinal centers is present, justifying the synonym papillary cystadenoma lymphomatosum (Figure 2-15). It may be bilateral in a small but significant number of cases. The extremely rare oncocytic carcinoma has an infiltrative growth pattern and an aggressive clinical behavior.

Malignant salivary gland tumors account for approximately 7 percent of all carcinomas arising in the upper aerodigestive tract.22 Risk factors include exposure to radiation, tobacco, chemicals, and viruses, and genetic predisposition. About 15 percent of all parotid, 35 percent of submandibular, 45 percent of minor salivary and 80 percent of sublingual gland tumors are malignant.23 Men and women are almost equally affected. In most instances, the clinical stage of the disease has greater influence on prognosis than the histologic grade, except in mucoepidermoid and adenocarcinoma, not otherwise specified.

Mucoepidermoid Carcinoma

The most frequent site for a mucoepidermoid carcinoma is the parotid, followed by intraoral minor salivary glands. Most patients are in their early fifties. Grossly, the tumor is poorly circumscribed and measures from 3 to 5 cm. The cut surface is solid but may be cystic. The tumor is composed of glandular and epidermoid cells, the latter characteristically of intermediate basaloid type (Figure 2-16). The histo-logic grading scheme is prognostically significant. Low-grade tumors form cysts lined by a single layer of glandular mucinous cells with an admixture of

Nasopharyngeal Goblet Cell Cyst
Figure 2-14. Oncocytoma. The tumor is solid with sheets of cells with abundant aci-dophilic cytoplasm. The nuclei have characteristic prominent nucleoli.
Papillary Nasopharyngeal Carcinoma
Figure 2-15. Warthin's tumor. The lesion is predominantly cystic with an exuberant lymphoid follicular reaction. The cyst is lined by oncocytic cells which are arranged in papillary structures.

epidermoid cells. The epidermoid and intermediate basaloid-type cells tend to form solid areas in intermediate grade, and predominate in high-grade lesions along with scant evidence of glandular differentiation, increased cytologic atypia, mitosis, necrosis and perineural invasion. Using these grading criteria, 90 percent of the low-grade as compared to 42 percent of the high-grade mucoepidermoid carcinoma patients were found to be alive at 10 years after treatment.24 An important differential diagnosis is primary or metastatic squamous cell carcinoma, which is rare in the parotid and lacks intracellular mucin. Sebaceous and clear cell neoplasms are additional differential diagnostic concerns.

Adenoid Cystic Carcinoma

The most frequent site of origin of adenoid cystic carcinoma is in the minor salivary glands, especially in the palate, followed by the sinuses and nasal cavity and the parotid glands. The patients are usually in their fifties and may be of either sex. On microscopic examination, the tumor has a characteristic cribriform appearance formed by the interruption of sheets of tumor cells by cylindrical pseudo-spaces or pseudo-lumina, giving rise to the designation cylin-droma (Figure 2-17). Although clinically indolent, these tumors are relentlessly infiltrative with a local recurrence rate of 47 percent. Perineural invasion is frequent and extensive, requiring intraoperative assessment of the neural margin of resection. Distant metastasis has been reported in 38 percent of cases with lung and bones being common sites. The microscopic grading system does not appear to be useful. Clinical stage is the most important factor in determining prognosis.25

Polymorphous Low-Grade Adenocarcinoma

This tumor is increasingly being recognized as one of the more frequent salivary gland adenocarcinomas ever since it was described under synonyms such as lobular, terminal duct or trabecular carcinoma.26,27 The patients usually are in their fifth decade. The tumors involve the minor salivary glands almost exclusively, and rarely, the nasal cavity or nasopharynx. The lesion may be relatively well-circumscribed but can extensively invade the adjacent bone. Microscopically, there is great architectural diversity (Figure 2-18). A single file arrangement may be seen as in the infiltrating lobular carcinoma of breast. In spite of their low-grade, usually indolent biologic behavior, 76 percent show perineural invasion and up to 29 percent may metastasize to the cervical lymph nodes.28 Differential diagnosis includes adenoid cystic carcinoma and pleomorphic adenoma.

Acinic Cell Carcinoma

Acinic cell carcinoma (ACC) comprises 17 percent of primary malignant salivary gland tumors.25 Almost 90 percent of them arise in the parotid gland, making it the second most common malignant tumor at this site. The age varies widely with a small peak in the fourth decade. Grossly, the tumor usually measures less than 3 cm, and is well-defined with a friable, tan cut surface. The most characteristic tumor cells are the acinic cells which contain periodic acid Schiff's reagent (PAS)-positive cytoplas-mic glycogen granules resembling the serous cells of salivary glands (Figure 2-19A). Histologic features used for grading are increased mitosis, necrosis, neural invasion, infiltration, pleomorphism and stromal hyalinization. Although the histologic grading system is not always useful, the conventional ACC should be separated from the papillocystic variant (Figure 2-19B) believed to have a particularly bad prognosis, and a highly aggressive dedifferentiated variant.29,30 The conventional ACC is a low-grade malignant tumor characterized by prolonged disease-free survival, late recurrences and late distant metastasis to bone, lung and brain.31

Adenocarcinoma, Not Otherwise Specified

These are adenocarcinomas lacking any characteristic feature that helps in classifying them as other specific types of epithelial tumors of salivary origin. Thus, it is a diagnosis by exclusion. There is a slight

Figure 2-16. A, A partly cystic mucoepider-moid carcinoma involving a dilated minor salivary gland duct. Although the tumor forms numerous cysts, the solid areas indicate its intermediate grade. B, The intracytoplasmic, as well as extracytoplasmic, neutral mucin stains bright pink with mucicarmine stain. The former is diagnostic of mucoepidermoid carcinoma.

Figure 2-17. Adenoid cystic carcinoma showing tumor cell nests with a cribriform/cylindromatous pattern. The pseudolumina may contain acidic mucin (as in this figure) or basement membrane-like material which may also surround tumor nests. The pseudolumina shows two layers of tumor cells with small, cuboidal cells towards the center and clear myoepithelial cells at the periphery.

Figure 2-17. Adenoid cystic carcinoma showing tumor cell nests with a cribriform/cylindromatous pattern. The pseudolumina may contain acidic mucin (as in this figure) or basement membrane-like material which may also surround tumor nests. The pseudolumina shows two layers of tumor cells with small, cuboidal cells towards the center and clear myoepithelial cells at the periphery.

male preponderance with a median age of 58 years. The minor salivary glands are more frequently involved followed by the parotid glands. Microscopically, the cells may display a glandular, papillary or mucinous growth pattern, and sometimes even resemble colonic adenocarcinoma. The histologic grading which takes into account cytologic atypia, pleomorphism, mitosis and necrosis, identifies low, intermediate and high grades. Prognosis depends on site (better in oral cavity tumors), histologic grade and clinical stage.32

Rare Tumors

Myoepithelioma and myoepithelial carcinoma are rare neoplasms composed almost entirely of myoepithelial cells. The parotid is the most common site. Multiple recurrences, distant metastasis and death due to disease occur in one-third of the patients suffering from myoepithelial carcinoma, suggesting an intermediate- to high-grade malignant potential.31 Epithelial-myoepithelial carcinoma is an uncommon, low-grade, multilobular, malignant neoplasm that shows both epithelial and myoepithelial differentiation and occurs most commonly in the parotid glands of elderly women. Clear cell adenocarcinoma occurs in the fifth to seventh decade and is comprised of

Spindle Cell Carcinoma Oral Cavity
Figure 2-18. Polymorphous low-grade adenocarcinoma. The squamous mucosa of the oral cavity is visible above. The tumor cells are squamoid near the surface and become clear and form glandular structures below.

glycogen-rich cells. It affects both sexes equally. Lymphoepithelial carcinoma may arise in the salivary glands, usually de novo but sometimes in association with Sjögren's syndrome. A female predilection and a higher incidence among the Inuit is noted.33 The parotid is the most frequently involved salivary gland. The morphology is similar to the nasopharyngeal variant—metastasis from which should be ruled out before considering a primary parotid tumor. Salivary duct carcinoma is a very aggressive neoplasm that resembles intraductal carcinoma of the breast replete with comedo-necrosis, "Roman bridges" and cribriform pattern. Most tumors occur in the parotid glands of elderly men.31 Perineural and vascular invasion and dense fibrosis are commonly present. Primary squamous cell carcinoma of the salivary gland is a rarity. It probably arises in the part of the excretory salivary duct which is closer to the oral cavity. A prerequisite for diagno sis is ruling out mucoepidermoid carcinoma and metastatic squamous cell carcinoma. Cystadenoma and cystadenocarcinoma are rare tumors characterized by cysts lined by columnar cells and resemble their counterparts in the pancreas and ovary.31

TUMORS OF THYROID AND PARATHYROID GLANDS

Thyroid tumors affect females more often than men. Radiation is an important predisposing factor, especially for papillary thyroid carcinoma. A close association of Hashimoto's thyroiditis to many thyroid malignancies, eg, lymphoma, papillary and Hurthle cell carcinoma, sclerosing mucoepidermoid thyroid carcinoma and squamous cell carcinoma has been noted. Malignant cells arising in the follicular epithelium express thyroglobulin, a feature that may be used to support their thyroid origin at metastatic sites.

Figure 2-19. A, Acinic cell carcinoma—conventional type. The tumor is predominently solid with microcyst formation. Several tumor cells have the typical granular cytoplasm of serous acinic cells. B, Acinic cell carcinoma—papillocystic variant. The tumor is predominantly cystic with papillary proliferation in the cyst lumen. This variant is believed to have a poorer prognosis than the conventional type.

Figure 2-19. A, Acinic cell carcinoma—conventional type. The tumor is predominently solid with microcyst formation. Several tumor cells have the typical granular cytoplasm of serous acinic cells. B, Acinic cell carcinoma—papillocystic variant. The tumor is predominantly cystic with papillary proliferation in the cyst lumen. This variant is believed to have a poorer prognosis than the conventional type.

Papillary Carcinoma

This is the most common thyroid carcinoma affecting patients at a young age. The size of the tumor varies widely from microscopic to massive tumors that may completely replace the thyroid and extend outside of it. Incidental or occult presentation and multifocality is well known. The characteristic nuclear features (Figure 2-20A), when present, are sufficient for the diagnosis of papillary carcinoma, even in the presence of a capsule and in the absence of invasion. Psammoma bodies may be present in nearly half of the cases. The nuclear morphology, papillary tissue fragments and psammoma bodies can also be appreciated in fine-needle aspiration cytology facilitating correct diagnosis. Several his-tologic variants have been described. The conventional papillary carcinoma with true papillae, and the follicular variant recapitulating the follicular architecture of the thyroid gland, have similar biologic behavior and a good prognosis (see Figure 2-20). The size of the papillary microcarcinoma is by definition less than 1 cm. It is usually incidentally discovered in association with a fibrous scar and has an excellent prognosis as has the encapsulated variant. The diffuse sclerosing variant is characterized by the patient's younger age, extensive involvement of the thyroid gland with a predominantly fibrosing, psammomatous papillary carcinoma with frequent squamous metaplasia, lymphocytic infiltration and vascular invasion. More than half of the patients develop regional lymph node involvement, and metastasis to lungs are frequent. In spite of the higher incidence of distant metastasis, death rate due to tumor is extremely low.34 The tall cell (Figure 2-21) and columnar cell variants have extremely poor prognosis.3536 The former occurs in older patients and presents with large tumor size while the

Figure 2-20. A, Papillary thyroid carcinoma—conventional type with well-formed papillae with fibrovascular cores. A psammoma body is seen in the upper right corner. The surrounding non-neoplastic tissue shows lymphocytic thyroiditis with which it is commonly associated. Inset shows the characteristic nuclear clearing, overlapping nuclei ("eggs in a basket") and nuclear grooves. B, Papillary carcinoma—follicular variant. The diagnosis is based on the similarity of nuclear features to conventional papillary carcinoma. A psammoma body is seen in the upper left corner.

Figure 2-20. A, Papillary thyroid carcinoma—conventional type with well-formed papillae with fibrovascular cores. A psammoma body is seen in the upper right corner. The surrounding non-neoplastic tissue shows lymphocytic thyroiditis with which it is commonly associated. Inset shows the characteristic nuclear clearing, overlapping nuclei ("eggs in a basket") and nuclear grooves. B, Papillary carcinoma—follicular variant. The diagnosis is based on the similarity of nuclear features to conventional papillary carcinoma. A psammoma body is seen in the upper left corner.

latter is reported in young men who die of disease within 2 years of presentation. Other morphologic indicators of poor prognosis are extra-thyroidal extension and vascular invasion. A cribriform-moru-lar variant has been described in young women in association with familial adenomatous polyposis.37

Follicular Neoplasm

Follicular adenoma is a benign, solitary, encapsulated tumor of the thyroid follicular epithelium. Fol-licular carcinoma is a malignant neoplasm which is distinguished from its benign counterpart by the presence of vascular and full-thickness capsular invasion into the surrounding non-neoplastic thyroid parenchyma (Figure 2-22). Thus, all follicular

Figure 2-21. Papillary carcinoma—tall cell variant. The cells are twice as tall as broad while the nuclear features remain the same as in papillary carcinoma. This morphologic variant is believed to have a worse prognosis than the conventional papillary thyroid carcinoma.

lesions should be completely excised with their capsule and the adjacent thyroid, so as to permit histologic evaluation of the entire capsule for infiltration. For this reason, distinction between follicular adenoma and carcinoma cannot be made on fine-needle aspiration cytology. Mitosis and nuclear atypia may be present in adenomas which are then designated atypical follicular neoplasms, the overwhelming majority of which behave in a benign fashion. Most patients with follicular carcinoma are in their fifth decade of life and present with a solitary neck mass. Blood-borne metastasis to lungs and bones is more common than lymphatic spread to regional nodes. A minimally invasive (encapsulated) follicular carcinoma needs to be distinguished from an extensively invasive one, as fewer than 5 percent of the former

Rthle Cell Carcinoma
Figure 2-22. Hürthle cell carcinoma—minimally invasive. The tumor cell cytoplasm is deeply acidophilic. Although the fibrous capsule is present all around the tumor, at this focus the tumor shows vascular invasion.

metastasize.38,39 In the encapsulated variant, capsular invasion in the absence of vascular invasion has little value in predicting outcome. Figure 2-23 schematically enumerates all follicular neoplasms in order of their malignant potential.

Hurthle Cell Neoplasms

Hurthle cell or oncocytic neoplasms are composed of cells with abundant pink (oxyphilic) cytoplasm containing ample abnormal mitochondria on ultrastructural examination. The majority of these tumors are benign. The lesion is often divided into lobules by thick fibrous septa. As in follicular carcinoma, presence of capsular or vascular invasion is a prerequisite for the diagnosis of malignancy (see Figure 2-22). As a result, fine-needle aspiration cytology can at best suggest a Hurthle cell neoplasm, but cannot distinguish between a benign or malignant lesion. These tumors tend to occur in an older age group with only a slight female preponderance. They are more aggressive than the conventional papillary or follicular carcinomas, suggesting an intermediate-grade malignant behavior.40

Poorly-Differentiated (Insular) Carcinoma

This tumor is viewed as a poorly-differentiated variant of the well-differentiated papillary or follicular thyroid carcinoma and occurs in a relatively older age group. The tumor cells are uniformly small with mild atypia and variable mitosis. Focal necrosis may be present. The cells are arranged in a solid or micro-follicular, nested or insular pattern. They express thyroglobulin which is useful in distinguishing them from medullary carcinoma. The biologic behavior is aggressive, resulting in recurrences and distant metastases (Figure 2-24).

Undifferentiated/Anaplastic Carcinoma

This is a high-grade malignant neoplasm which usually affects older patients and has a female preponderance. Patients present with a recent-onset rapidly-enlarging mass frequently associated with dyspnea, dysphagia and/or hoarseness, indicating extra-thyroidal extension at presentation. Histologi-cally, the tumor may be composed of three types of

Follicular Adenoma

Atypical Follicular Adenoma

Follicular Neoplasm ctf Uncertain Malignant Potential

(Follicular NUMP)

Follicular Carcinoma Minimally Invasive

Follicular Carcinoma -Widely Invasive

Benign

Completely fcncapsulatcd _

Vast majority henign ~ -. Completely encapsulated but Cellular atypia & ___

Majority benign Encapsulated but

Microscopic small capsular invasion Mo vascular Invasion

Metastasis in < 5% Encapsulated but

Microscopic small capsular invasion Focal vascular invasion must

Increased metastatic potential Capsular destruction must Vascular invasion usual

Figure 2-23. Follicular neoplasms arranged in order of worsening prognosis from above down.

Figure 2-23. Follicular neoplasms arranged in order of worsening prognosis from above down.

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Figure 2-24. Poorly-differentiated carcinoma of thyroid with an insular and barely discernible micro-follicular growth pattern. This tumor showed nuclear features of papillary carcinoma at higher magnification, suggesting that it may have progressed from a well-differentiated papillary carcinoma.

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Figure 2-24. Poorly-differentiated carcinoma of thyroid with an insular and barely discernible micro-follicular growth pattern. This tumor showed nuclear features of papillary carcinoma at higher magnification, suggesting that it may have progressed from a well-differentiated papillary carcinoma.

Cancer Tumors Body

Figure 2-25. Anaplastic carcinoma of the thyroid. The tumor cells are spindle-shaped with markedly anaplastic nuclei resembling a high-grade sarcoma. Due to their extreme degree of dedifferentiation, the tumor cells do not (or only focally) express thyroglobulin, requiring a combined clinicopathologic effort to make a definite diagnosis of primary thyroid carcinoma.

Figure 2-25. Anaplastic carcinoma of the thyroid. The tumor cells are spindle-shaped with markedly anaplastic nuclei resembling a high-grade sarcoma. Due to their extreme degree of dedifferentiation, the tumor cells do not (or only focally) express thyroglobulin, requiring a combined clinicopathologic effort to make a definite diagnosis of primary thyroid carcinoma.

cells: anaplastic spindle cells resembling a sarcoma, bizarre pleomorphic multinucleate giant cells and squamoid cells (Figure 2-25). Severe nuclear atypia, cellular pleomorphism, brisk mitosis, large foci of necrosis and extensive invasion are characteristic features. Rarely, metaplastic bone or cartilage may be present. Immunohistochemically, thyroglobulin expression is variable—usually weak or even negative. The undifferentiated carcinomas may arise from dedifferentiation in a well-differentiated papillary or follicular carcinoma (Figure 2-26). The tumor metastasizes widely using both blood and lymphatic vessels. All patients die, mostly due to respiratory compromise caused by the tumor.

Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid. It accounts for less than 10 percent of all thyroid malignancies. Characteristically, MTCs secrete calcitonin, produce amyloid and, in about 20 percent of cases, are familial. In the latter situation, it may be inherited in an autosomal dominant manner either in association with multiple endocrine neoplasia (MENIIa and MENIIb) syndromes or as familial MTC, and affects children and adolescents with an equal gender distribution. Mutations in the RET proto-oncogene on chromosome 10

have been found to be associated with all familial and some sporadic cases.41 The tumor usually involves the upper two-thirds of the thyroid, the area of maximum concentration of C cells in the normal gland. The sporadic cases are unifocal and discrete while the familial cases are more likely to be multi-focal and involve both lobes. Less than 50 percent of tumors contain the characteristic stromal amyloid which may be focally calcified (Figure 2-27). Immunohistochemistry shows that the tumor cells and sometimes the stromal amyloid are positive for calcitonin (Figure 2-28). The tumor cells also

Well-Differentiated Thyroid Carcinoma Papillary Carcinoma Follicular Carcinoma

Dedifferentiation Poorly-differentiated Carcinoma

Dedifferentiation

Anaplastic Carcinoma

Figure 2-26. Schematic diagram showing possible progression of well-differentiated thyroid carcinoma to anaplastic carcinoma.

express calcitonin gene-related peptide and carci-noembryonic antigen, and are negative for thyroglob-ulin. However, immuno-stain for chromogranin, a marker for neuroendocrine differentiation, is more sensitive than calcitonin for MTC. Ultrastructurally, multiple intracytoplasmic membrane-bound secretory granules are demonstrated. It is possible to diagnose MTC by fine-needle aspiration because of the typical plasmacytic tumor cell morphology and demonstration of amyloid and calcitonin. The tumor tends to be indolent in familial MTC, and aggressive in sporadic MTC and MENIIb, leading to metastasis due to lymphatic and vascular invasion of cervical nodes, lung, liver and bone. Death is usually due to uncontrolled local disease. It is important to recognize a small cell (anaplastic) variant of MTC which resembles small (oat) cell neuroendocrine carcinoma

Insular Thyropid Carcinoma
Figure 2-27. Medullary carcinoma of the thyroid showing an insular pattern of growth interrupted by hyalinized fibrous septa which may contain amyloid.

of the lung. It is mitotically more active, less likely to produce calcitonin and amyloid, and is believed to have a slightly worse prognosis than the conventional MTC. Mixed medullary-follicular and medullary-papillary carcinomas have also been described.

Uncommon Tumors of the Thyroid

Primary squamous cell carcinoma is extremely rare in the thyroid. Direct extension from the larynx, metastasis, or a nonsquamous thyroid carcinoma, eg, papillary or undifferentiated carcinoma with extensive squamous metaplasia should be ruled out. Mucoepidermoid carcinoma in the thyroid is a rare, low-grade neoplasm postulated to arise as a meta-plastic change in the thyroid follicular epithelium. A sclerosing variant with eosinophilia has been described.42 Carcinoma showing thymus-like differentiation is a rare, low-grade tumor believed to arise in branchial pouch remnants capable of thymic differentiation with resemblance to a thymic carcinoma.43 Lymphomas of the thyroid are usually non-Hodgkin's lymphomas of B-cell type spanning the spectrum of low-grade to high-grade diffuse large cell type. The low-grade lymphomas are similar to the mucosa-associated lymphoid tissue lymphomas elsewhere in the body. Frequent association with Hashimoto's thyroiditis is noted. Transformation of low- to high-grade lymphoma is well documented.

Parathyroid Adenoma and Carcinoma

Parathyroid adenoma is a solitary, well-defined, hyperfunctional benign neoplasm which accounts for the majority of cases of primary hyperparathy-roidism. Its distinction with hyperplasia is important for correct surgical management, as the former is treated by removal of only the adenomatous gland while the latter requires resection of all four glands. The distinction between normal and hyperplastic glands is made by weight as the histologic appearance may be similar. Most adenomas are composed of chief cells which completely replace the intraglandular fat that is present in normal and hyperplastic glands. Ectopic adenomas may be found in association with the thymus in the mediastinum and in intrathyroidal locations. Extremely high serum calcium levels are generally indicative of

Borax For Ants Recipe
Figure 2-28. Immunohistochemistry for calcitonin highlights a metastatic focus of medullary carcinoma in a lymph node.

parathyroid carcinoma. This is an infiltrative tumor characterized by vascular and capsular invasion, dense fibrosis, nuclear atypia, increased mitosis and regional and distant metastasis (Figure 2-29).

NEURONAL, NEUROENDOCRINE AND NEUROECTODERMAL TUMORS

Paraganglioma

Extra-adrenal paragangliomas can occur in the head and neck. They secrete norepinephrine and are functional. Patients (most of whom are adults) present with hypertensive headaches, tachycardia and sweating. The carotid body tumors occur at the bifurcation of the carotid artery. The jugulotympanic paragan-glioma (glomus jugulare tumor) may present as mass in temporal bone extending to the middle ear or external auditory canal or involve the jugular bulb in the jugular foramen. There is a female predilection. Angiographic findings are characteristic as the tumor is very vascular. Because of poor accessibility in the jugulotympanic region, the tumors are removed in a piece-meal fashion destroying the typical "zellballen" arrangement of the tumor cells, making histologic diagnosis difficult (Figure 2-30A). The cells express several neuroendocrine markers by immunohistochemistry and contain

Insular Thyroid Carcinoma Pathology

Figure 2-29. Parathyroid carcinoma in a 51-year-old man with hyper-parathyroidism. The cells have uniform morphology and frequent cyto-plasmic clearing. The tumor invaded blood vessels, adjacent soft tissue, and thyroid gland in other sections. Immunostaining with anti-parathyroid hormone antibody is characteristically positive (inset).

Figure 2-29. Parathyroid carcinoma in a 51-year-old man with hyper-parathyroidism. The cells have uniform morphology and frequent cyto-plasmic clearing. The tumor invaded blood vessels, adjacent soft tissue, and thyroid gland in other sections. Immunostaining with anti-parathyroid hormone antibody is characteristically positive (inset).

dense core neurosecretory granules on ultrastructural examination (Figure 2-30B). Ten percent of these tumors metastasize. Histologic criteria such as nuclear atypia, pleomorphism and mitosis are not reliable in predicting malignant behavior. The vagal paraganglioma may be seen in association with the vagus nerve in the anterolateral portion of the neck.

Olfactory Neuroblastoma

Olfactory neuroblastoma or esthesioneuroblastoma is a rare malignancy with a bimodal age distribution in adolescents and adults and without any gender predilection. It is believed to arise in the specialized neurosecretory cells of the olfactory mucosa in the

Figure 2-30. A, Paraganglioma—carotid body tumor. The cells have moderate-to-abundant cytoplasm, and are arranged in well-defined nests ("zellballen"). There is occasional binucleation and nuclear atypia. Cytologic criteria are of no help in predicting biologic behavior. B, Intense and diffuse cytoplasmic staining of tumor cells with anti-chromogranin antibody by immunohistochemistry supporting their neuroendocrine nature.

superior one-third of the nasal septum, superior turbinate and the cribriform plate, which may be broken with intracranial extradural extension of the tumor. The usual presentation is as a polypoid nasal mass with epistaxis and nasal obstruction, usually of long duration. Microscopically, the tumor is submu-cosal and is composed of nests of monomorphous cells in a fibrillary background of neuropil (Figure 2-31 A). Immunohistochemically, the tumor cells are positive for neural and neuroendocrine markers, eg, synaptophysin, neurofilament protein, and chro-mogranin among others (Figure 2-31B). Ultrastructural examination can help in the differential diagnosis by demonstrating neurosecretory granules, microtubules and neuritic processes. We believe that

Olfactory Neuroblastoma Histology

the olfactory neuroblastoma is different from Ewing's sarcoma/primitive neuroectodermal tumors at both the molecular and immunohistochemical level.44 Higher incidence of S100 protein expression and low expression of Ki 67, a cell proliferation marker, have been linked to better survival.45 Most tumors are slow growing, locally destructive and have a favorable prognosis although regional and distant metastasis can occur at prolonged follow-up.

Ewing's Sarcoma/Primitive Neuroectodermal Tumor

Skeletal or extraskeletal Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is extremely rare in the head and neck. It is characterized by the chromosomal translocation t(11:22)(q24;q12) leading to the EWS/FLI1 fusion protein MIC2 which can be detected immunohistochemically by O13 (CD99) antibody.44 Metastasis should be ruled out before considering the lesion as a primary tumor in the head and neck.

Neuroendocrine Carcinoma

Small cell neuroendocrine carcinoma is extremely rare in the head and neck and may be seen in the nasal cavity, paranasal sinuses, salivary or thyroid glands. It resembles the small (oat) cell carcinoma of the respiratory tract. The tumor cells are positive for markers wwà

Figure 2-31. A, Olfactory neuroblastoma showing a cellular small blue cell neoplasm in a fibrillary background of neuropil. Homer-Wright rosettes formed by the arrangement of tumor cells around central neurofibrillary collections are seen. B, Immunohistochemistry with S100 protein shows staining of sustentacular cells around the periphery of tumor cell nests, an important feature in the differential diagnosis with other relatively high-grade neuroendocrine/ neuroectodermal neoplasms in this area.

Merkel Cell Nose

of neuroendocrine differentiation and cytokeratin. In the nose, it needs to be distinguished from an olfactory neuroblastoma because of different prognosis and management. In the thyroid, lack of calcitonin expression and amyloid production are helpful hints to distinguish it from medullary carcinoma.

Merkel cell carcinoma (MCC) is a variant of neuroendocrine carcinoma of the dermis and subcutaneous tissue. There is a male predilection with a median age of 70 years. Most MCCs arise in the skin of the head and neck. They differ from the small cell neuroendocrine carcinoma in having a distinct pale nucleus with fine speckled chromatin, a characteristic perinuclear dot-like reaction with cytokeratin 20 and neurofilament protein46 on immunohistochem-istry (Figures 2-32 and 2-33.). This is a high-grade tumor and has rarely been reported in the salivary gland and oral mucosa.

Malignant Melanoma

Head and neck melanomas can be categorized into cutaneous and mucosal types. Cutaneous melanomas occur most commonly in the face, followed by scalp, neck and external ear in decreasing order of frequency. They have a slightly worse prognosis than similar lesions outside of the head and neck. The tumor may be in the radial growth phase which is completely excisable and therefore curable, and/or in the vertical growth phase. In the latter, the malignant cells invade and grow within the dermis and acquire metastatic potential The two phases are clinically definable. The superficial spreading melanoma is an in situ, and usually microinvasive, radial growth phase malignant melanoma etiologically associated with recreational sun exposure (Figure 2-34A). Lentigo maligna is usually in situ and occurs in the background of epidermal atrophy and severe sun damage as a result of chronic exposure in an elderly person. If invasion is also present, the diagnosis is lentigo maligna melanoma (Figure 2-34B). In contrast, the nodular melanoma is completely within the dermis without any associated radial growth phase and needs to be differentiated from metastatic melanoma. The cells may be epithelioid or spindle-shaped giving the tumor a biphasic appearance. Immunohistochemically, malignant melanoma stains diffusely for S100 protein, and markers for melanocytic differentiation gp-100 (HMB 45) and Melan-A/ MART-1.47 The clinical outcome depends upon several clinical criteria, eg, age, sex (younger and female patients have a better outcome than older and males), location (neck and ear better than scalp and face) and several histopathologic criteria enumerated in Table 2-3. Of these, the thickness of the lesion and Clark's level are the most powerful predictors of outcome (Figure 2-35).49 In the radial growth phase, regressive changes have a negative effect on survival. The desmoplastic melanoma is a spindle cell, collagen producing, usually amelanotic melanoma which is usually a vertical growth phase tumor but may be associated with a radial growth phase (Figure 2-36). The prognosis is good despite a tendency to neurotropism (nerve invasion).

Merkel Cell Carcinoma Pictures Scalp
Figure 2-32. Merkel cell carcinoma in the skin showing nests of small blue cells.
Necrotic Cells Horses With Melanoma

Figure 2-33. A, Merkel cell carcinoma— higher magnification shows the typical hyper-chromatic endocrine type of nucleus, necrosis and brisk mitosis. S, Immunostain with neurofilament shows characteristic dot-like positivity in the paranuclear golgi area. Similar positivity is also seen with cytokeratin (CK20).

Figure 2-33. A, Merkel cell carcinoma— higher magnification shows the typical hyper-chromatic endocrine type of nucleus, necrosis and brisk mitosis. S, Immunostain with neurofilament shows characteristic dot-like positivity in the paranuclear golgi area. Similar positivity is also seen with cytokeratin (CK20).

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Figure 2-34. A, Cutaneous superficially-spreading malignant melanoma in situ (Clark level 1). Single cell proliferation of malignant melanocytes is seen in contact wi

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